title: Altered Hippo signalling in polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive deterioration of renal function and formation of cysts, and is an important cause of end-stage renal disease. Previously we showed that tubular epithelial injury accelerates cyst formation in inducible Pkd1-deletion mice. In these mice, expression of the planar cell polarity (PCP) component Four-jointed (Fjx1) is decreased during epithelial repair, while in control mice Fjx1 expression is increased and may be required during tissue regeneration. In cystic kidneys, however, Fjx1 expression is also increased. Besides a PCP component, Four-jointed is also implicated in the Hippo-signalling pathway. This pathway is involved in organ size control by regulating proliferation and apoptosis. The role of Hippo signalling, together with the opposing expression pattern of Fjx1 during epithelial repair and at cystic stages, triggered us to investigate the activity of the Hippo pathway during these processes. Therefore, we examined its final effector molecule, the transcriptional co-activator Yes-associated protein (YAP) and observed that during tissue repair, YAP expression was not different between Pkd1-deletion mice and controls, ie during tissue regeneration YAP expression was increased and predominantly localized in the cytoplasm but normalized after tissue repair. At a later stage, however, in cystic epithelia and epithelia of dilated tubules, strong nuclear YAP accumulation was observed, accompanied by up-regulation of the YAP transcriptional targets Birc-3, Ctgf, InhbA, and Fjx1. Altered activity of the Hippo pathway was confirmed in renal tissues from human ADPKD and ARPKD patients, as well as in cystic renal tumours. Our data strengthen the concept that during epithelial repair Four-jointed is involved in PCP signalling, while in cystic kidneys it is related to Hippo signalling and cyst growth.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: Happé
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: van der Wal
authors.forename: Wouter N
authors.initials: WN
authors.lastname: Leonhard
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kunnen
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000502:physiology; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels / Q000172:deficiency / Q000502:physiology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D003545:Cysteine; D051575:Proto-Oncogene Proteins c-yes; D050396:TRPP Cation Channels; C039961:S-(1,2-dichlorovinyl)cysteine